The development of atherosclerosis and vascular disease is a multifaceted process that involves both genetic and environmental factors which interact in complex ways. The unique interactions of these different factors in any individual can promote the dysregulation of specific physiologic pathways, which in turn can then affect other physiologic systems. This program project will explore the boundary between three prominent physiologic systems whose involvement in vascular disease is well established. These systems are; thrombosis/fibrinolysis, inflammation, and lipid metabolism, and each has been independently linked with the development of vascular disease. More recent studies have suggested that the roles that each of these systems play in the development of vascular disease may not be independent of one another and that previously unrecognized interactions or cross-talk between these three systems can dramatically influence disease progression. For example, thrombosis can both provoke acute vascular events, and initiate longterm changes in the vascular bed that lead to the development of ischemic disease. Inflammation, in turn, is known to promote thrombosis, while hyperlipidemia is known to promote inflammation. However, beyond these known correlations new data are beginning to show specific molecular interactions that span these three systems. One molecule in particular that has been identified as playing a role in both inflammation and thrombosis is plasminogen activator inhibitor-1 (PAI-1), and very recent data suggests that PAI-1 may also play a role in regulating lipid metabolism. Therefore, this application will create an integrated program that will test the hypothesis that specific molecular events regulate cross-talk between thrombosis, inflammation, and lipid metabolism that significantly influence vascular disease progression. Each project is based on the diverse strengths of each of the investigators and seeks to identify specific points of interaction between these varied systems, and then to characterize the specific molecular events associated with these interactions. This application consists of 4 projects and three cores to support these projects. The primary goals of each project are: project 1- characterize the role of PAI-1 in lipid metabolism; project 2- examine the role of PAI-1 in venous thrombogenesis; project 3- investigate the thrombotic/fibrinolytic balance in coronary transplant vasculopathy; and project 4- Identify thrombosis modifier genes and novel anticoagulants In zebrafish. The successful implementation of these goals should lead to a better understanding of the etiology of vascular disease and ultimately to improved treatments of thrombosis and vascular disease.